Malaria still afflicts about half of the world population causing more than 500,000 deaths, mostly children. The global economic toll of malaria is enormous. Most of the drugs that are currently utilized for malaria treatment are losing their effectiveness due to widespread emergence of drug resistance. Even artemisinin-based combination treatments (ACTs) that are the front-line therapies against falciparum malaria are showing signs of resistance in endemic regions of Southeast Asia. Therefore, it is urgent to identify new drug leads acting on novel targets for the development of next generation of therapies against malaria. We have screened cheminformatics-selected 2,115 unique scaffolds from a BioDesign library that incorporates privileged features of pharmacologically relevant natural products for antiplasmodial activities. This screen has identified two scaffolds that exhibit potent antimalarial activity, act early on parasite's asexual life cycle, including invasion. The proposed research project seeks to establish and further develop these two novel antimalarial chemotypes. We hypothesize that these chemotypes will be excellent platforms for hit-to-lead optimization studies that will yield effective antimalarial lead compounds targeting cellular mechanisms distinct from current malaria drugs. To accomplish the objective of developing new malaria therapeutics and prove our hypothesis, we plan to: (a) Design and synthesize early-acting lead compounds through structure-activity and structure-property relationship studies. (b) Determine stage-specific action, resistance profile, pharmacological properties, in vivo pharmacokinetics, toxicology, and antimalarial efficacy. (c) Determine molecular targets of the scaffolds by whole genome sequencing of resistant lines. The proposed research is highly significant because at the end of the project we expect to have novel antimalarial lead compounds with defined mechanism of action.